PROJECT SUMMARY/ABSTRACT Knee osteoarthritis (KOA) is one of the leading causes of chronic pain and disability worldwide, affecting over 30% of older adults and represents a major global health and economic burden to individuals and society. The rates of KOA have more than doubled in the past 70 years and continue to grow sharply, given increases in life expectancy and population BMI. Surgery is often employed to treat KOA, but it associated with a high rate of persistent pain, and is not a permanent solution. Numerous nonsurgical therapies have been advocated to treat pain in patients with KOA. However, stand-alone conservative treatments including non-opioid medications and joint injections provide only limited pain relief and functional improvement in a subset of knee OA sufferers. This has led to a high rate of opioid use in this population. The overarching goal of this proposal is to conduct a sequential parallel group randomized controlled trial (RCT) to rigorously evaluate the comparative-effectiveness of conservative behavioral and non-opioid pharmacological treatments (Phase I) and, among non-responders, the benefits of nonsurgical procedural interventions (Phase II) in three inter- related Aims. Aim 1 will evaluate the effectiveness of individual and combined online cognitive behavioral therapy (PainTRAINER) and pharmacologic treatment (duloxetine) in improving pain and function for KOA patients compared to standard of care. Aim 2 will determine if genicular nerve radiofrequency ablation (RFA) or intra-articular injection of hyaluronic acid and steroid are more effective in improving outcomes than local anesthetic nerve block or SOC and help establish the role of these interventional treatments in the overall management of pain in KOA patients. Patients that have failed Phase I treatment will be provided with an opioid for severe pain management, if appropriate, allowing us to examine the opioid-sparing effects of these procedures in a subset of participants. Aim 3 will test whether clinical and psychosocial phenotypes predict short- and long-term treatment response. Our study involves comprehensive and innovative approaches that have never before been employed in this context, including: a multidisciplinary cadre of investigators conducting the largest randomized trial to date evaluating behavioral, pharmacotherapy and nonsurgical procedural interventions for KOA; a stepped-care, factorial design model that allows for more than two dozen pair-wise treatment comparisons; phenotyping to identify responders and improve selection for each therapy (i.e. precision medicine), which is expected to refine outcomes and reduce unnecessary interventions. The results, which will follow pragmatic principles in order to maximize the information provided to stakeholders, will examine not only the effectiveness of each tested intervention but also provide meaningful information regarding effectiveness across key subgroups of patients. The knowledge gained will contribute to the development of translatable therapeutic strategies for the treatment of patients with KOA pain that will lead to opioid sparing effects.